Devices and methods for treatment of heart failure by splanchnic nerve ablation

ABSTRACT

A method for treating a heart failure patient by ablating a nerve of the splanchnic sympathetic nervous system to increase venous capacitance and reduce pulmonary blood pressure. A method including: inserting a catheter into a vein adjacent the nerve, applying stimulation energy and observing hemodynamic effects, applying ablation energy and observing hemodynamic effects, applying simulation energy after the ablation and observing hemodynamic effects.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/510,503, filed Jul. 12, 2019, which is a continuation of U.S.application Ser. No. 15/017,351, filed Feb. 5, 2016, now U.S. Pat. No.10,376,308, which claims the benefit of U.S. Provisional PatentApplications 62/112,395, filed Feb. 5, 2015, and 62/162,266, filed May15, 2015, each of which is herein incorporated by reference in itsentirety.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare incorporated herein by reference in their entirety to the sameextent as if each individual publication or patent application wasspecifically and individually indicated to be incorporated by reference.

BACKGROUND

Heart failure (HF) is a medical condition that occurs when the heart isunable to pump sufficiently to sustain the organs of the body. Heartfailure is a serious condition and affects millions of patients in theUnited States and around the world.

In the United States alone, about 5.1 million people suffer from heartfailure and according to the Center for Disease Control, the conditioncosts the nation over $30 billion in care, treatments, medications, andlost production.

The normal healthy heart is a muscular pump that is, on average,slightly larger than a fist. It pumps blood continuously through thecirculatory system to supply the body with oxygenated blood. Underconditions of heart failure, the weakened heart cannot supply the bodywith enough blood and results in cardiomyopathy (heart muscle disease)characterized by fatigue and shortness of breath, making even everydayactivities such as walking very difficult.

Oftentimes, in an attempt compensate for this dysfunction, the heart andbody undergo physiological changes that temporarily mask the inabilityof the heart to sustain the body. These changes include the enlargementof heart chamber, increased cardiac musculature, increased heart rate,raised blood pressure, poor blood flow, and imbalance of body fluids inthe limbs and lungs.

One common measure of heart health is left ventricular ejection fraction(LVEF) or ejection fraction. By definition, the volume of blood within aventricle immediately before a contraction is known as the end-diastolicvolume (EDV). Likewise, the volume of blood left in a ventricle at theend of contraction is end- systolic volume (ESV). The difference betweenEDV and ESV is stroke volume (SV). SV describes the volume of bloodejected from the right and left ventricles with each heartbeat. Ejectionfraction (EF) is the fraction of the EDV that is ejected with each beat;that is, it is SV divided by EDV. Cardiac output (CO) is defined as thevolume of blood pumped per minute by each ventricle of the heart. CO isequal to SV times the heart rate (HR).

Cardiomyopathy, in which the heart muscle becomes weakened, stretched,or exhibits other structural problems, can be further categorized intosystolic and diastolic dysfunction based on ventricular ejectionfraction.

Systolic dysfunction is characterized by a decrease in myocardialcontractility. A reduction in the LVEF results when myocardialcontractility is decreased throughout the left ventricle. CO ismaintained in two ways: left ventricular enlargement results in a higherSV and an increase in contractility as a result of the increasedmechanical advantage from stretching the heart. However, thesecompensatory mechanisms are eventually exceeded by continued weakeningof the heart and CO decreases, resulting in the physiologicmanifestations of HF. The left side of the heart cannot pump with enoughforce to push a sufficient amount of blood into the systemiccirculation. This leads to fluid backing up into the lungs and pulmonarycongestion. In general terms, systolic dysfunction is defined as an LVEFless than 40% and heart failure in these patients can be broadlycategorized as heart failure with reduced ejection fraction (HFrEF).

Diastolic dysfunction refers to cardiac dysfunction in which leftventricular filling is abnormal and is accompanied by elevated fillingpressures. In diastole, while the heart muscle is relaxed the filling ofthe left ventricle is a passive process that depends on the compliance(defined by volume changes over pressure changes), or distensibility, ofthe myocardium or heart muscle. When the ventricles are unable to relaxand fill, the myocardium may strengthen in an effort to compensate topoor SV. This subsequent muscle hypertrophy leads to even furtherinadequate filling. Diastolic dysfunction may lead to edema or fluidaccumulation, especially in the feet, ankles, and legs. Furthermore,some patients may also have pulmonary congestion as result of fluidbuildup in the lungs. For patients with HF but without systolicdysfunction, diastolic dysfunction is the presumed cause. Diastolicdysfunction is characteristic of not only HCM, which is characterized bythe thickening of heart muscle, but also RCM, which is characterized byrigid heart muscle that cannot stretch to accommodate passive filling.In general terms, diastolic dysfunction is defined as a LVEF of greaterthan 40% and HF in these patients can be broadly categorized as heartfailure with preserved ejection fraction (HFpEF).

While a number of drug therapies successfully target systolicdysfunction and HFrEF, for the large group of patients with diastolicdysfunction and HFpEF no promising therapies have yet been identified.The clinical course for patients with both HFrEF and HFpEF issignificant for recurrent presentations of acute decompensated heartfailure (ADHF) with symptoms of dyspnea, decreased exercise capacity,peripheral edema etc. Recurrent admissions for ADHF utilize a large partof current health care resources and could continue to generate enormouscosts.

While the pathophysiology of HF is becoming increasingly betterunderstood, modern medicine has, thus far, failed to develop newtherapies for chronic management of HF or recurrent ADHF episodes. Overthe past few decades, strategies of ADHF management and prevention haveand continue to focus on the classical paradigm that salt and fluidretention is the cause of intravascular fluid expansion and cardiacdecompensation. Increasing evidence suggests that fluid homeostasis andcontrol of intravascular fluid distribution is disrupted in patientswith HF. Disregulation of this key cardiovascular regulatory componentcould not only explain findings in chronic HF but also in ADHF.Consequently, blocking of the autonomic nervous system to alter fluiddistribution in the human body could be used as a therapeuticintervention.

Additionally, the classical understanding of HF pathophysiologyemphasizes the mechanism of poor forward flow (i.e., low CO), resultingin neurohumoral, or sympathetic nervous system (SNS) up-regulation.However, new evidence emphasizes the concurrent role of backward failure(i.e., systemic congestion) in the pathophysiology and diseaseprogression of HF. Coexisting renal dysfunction with diuretic resistanceoften complicates the treatment of HF and occurs more frequently inpatients with increased cardiac filling pressures. Chronic congestiveheart failure (CHF) is characterized by longstanding venous congestionand increased neurohumoral activation. Critically important has been theidentification of the splanchnic vascular bed as a major contributor toblood pooling and cardiac physiology. Newly evolving methods and devicesinvolving sympathetic nervous system blocking and manipulation ofsystems including the splanchnic vascular bed have opened novel avenuesto approach the treatment of heart disease. In particular, the role ofsympathetic nerves that innervate smooth muscle in the walls ofsplanchnic veins have become better known. In the case of hyperactivityof these nerves they became a novel target in the treatment of CHF.

SUMMARY OF THE DISCLOSURE

In view of the foregoing, it would be desirable to provide an apparatusand methods to affect neurohumoral activation for the treatment of HFand particularly diastolic HF, (HFpEF).

The present invention may be used to provide an improved treatmentoption for patients suffering from HF by ablating the splanchnic nerves(e.g., greater, lesser and least) that innervate organs and vasculatureof the abdominal compartment and the greater splanchnic nerve (GSN) inparticular. By selectively ablating specific nerves, the inventionprovides a novel method and device that can affect circulating bloodvolume, pressure, blood flow and overall heart and circulatory systemfunctions. In this way, the present invention helps to introduce novelsolutions to treat HF and particularly HFpEF based on the mostcontemporary physiological theories regarding HF.

About 5% of the total body water is located within the vasculature inthe form of blood. The venous system contains approximately 70% of totalblood volume and is roughly 30 times more compliant than the arterialsystem. Venous compliance is a measure of the ability of a hollow organor vessel to distend and increase in volume with increasing internalpressure. A number of mechanisms are involved in regulation of volume,most importantly the neurohormonal system. On the arterial side, flowand resistance are regulated by resistance vessels. The sympatheticnervous system plays a major role in determining systemic vascularresistance (SVR) predominantly through activation and deactivation ofcardiopulmonary and arterial baroreflexes, as well as through changes incirculating norepinephrine.

Capacitance is a determinant of the venous vascular function and highervascular capacitance means more blood can be stored in the respectivevasculature. The autonomic nervous system is the main regulatorymechanism of vascular capacitance.

Circulating blood is distributed into two physiologically but notanatomically separate compartments: the “venous reservoir” and“effective circulatory volume”. The term “venous reservoir” (or“unstressed volume”) refers to the blood volume that resides mainly inthe splanchnic vascular bed and does not contribute to the effectivecirculating volume. The venous reservoir that is also referred to as“unstressed volume” or “vascular capacitance” can be recruited through anumber of mechanisms like activation of the sympathetic nervous system,drugs, or hormones.

The term “effective circulatory volume” (or “stressed volume”) refers toblood that is present mainly in the arterial system and innon-splanchnic venous vessels and is one of the main determinants ofpreload of the heart. The stressed blood volume and systemic bloodpressure are regulated by the autonomic nervous system of which thesympathetic nervous system is a part.

The unstressed volume of blood is mostly contained in the splanchnicreservoir or “splanchnic vascular bed”. The splanchnic reservoirconsists of vasculature of the visceral organs including the liver,spleen, small and large bowel, stomach, as well as the pancreas. Due tothe low vascular resistance and high capacitance the splanchnic vascularbed receives about 25% of the CO and the splanchnic veins containanywhere from 20% to 50% of the total blood volume.

Consequently, the splanchnic vascular bed serves as the major bloodreservoir, which can take up or release, actively and passively, themajor part of any change in circulating blood volume.

While experimenting with cadavers and animals inventors made twoimportant discoveries: (a) venous reservoir can be artificiallymanipulated and modified by selectively ablating or stimulating the GSN,and (b) in humans and some animals the GSN, although hidden deep in thebody, can be accessed very closely from superficial veins, through thevenous system, and the azygos veins.

Splanchnic veins are considerably more compliant than veins of theextremities. Animal and human studies demonstrate that the splanchnicreservoir can not only store considerable amounts of blood, but bloodcan also be actively or passively recruited from it into the systemiccirculation in response to variations of the venous return of blood tothe heart and physiologic need for heart preload. One of the maindeterminants of active recruitment is sympathetic nerve activity (SNA),which through hormones and a neurotransmitters epinephrine andnorepinephrine causes venoconstriction, thereby reducing splanchniccapacitance and increasing effective circulatory volume. This can beexplained by a large numbers of adrenergic receptors in the splanchnicvasculature that are sensitive to changes to the sympathetic nervoussystem. Compared with arteries, splanchnic veins contain more than five(5) times the density of adrenergic terminals. The consequence is a morepronounced venous vasomotor response in the splanchnic system comparedto other vascular regions.

The splanchnic vascular bed is well suited to accommodate and storelarge amounts of blood as well as shift blood back into activecirculation, naturally acting in a temporary blood volume storagecapacity. The high vascular capacitance allows the splanchnic vascularbed to maintain preload of the heart and consequently arterial bloodpressure and CO over a wide range of total body volume changes. Once thestorage capacity of the splanchnic vascular bed is reached, increases intotal body fluid express themselves as increased cardiac preload beyondphysiologic need and eventually extravascular edema and particularlyfluid accumulation in the lungs that is a symptom common in HF.

Increased activation of the sympathetic nervous system (SNS) and theneurohormonal activation along with increases in body fluids and saltshave long been debated as causes versus effects of HF. It has beenpreviously suggested that in HF redistribution of the splanchnicreservoir, driven by increased SNA to the splanchnic vascular bedleading to decreased venous compliance and capacitance, is responsiblefor increased intra-cardiac filling pressure (preload) in the absence ofincreases in total body salt and water. HF is marked by chronicover-activity of the SNS and the neurohormonal axis. It is now suggestedthat SNA and neurohormonal activation result in an increased vasculartone and consequently in decreased vascular capacitance of thesplanchnic vascular bed. While peripheral vascular capacitance is mostlyunchanged in HFpEF and HFrEF compared to controls, the vascularcapacitance of the splanchnic vascular can be significantly decreased.

So-called “acute HF” is initiated by a combination of two pathways:cardiac and vascular. The “cardiac pathway” is generally initiated by alow cardiac contractility reserve, while the “vascular pathway” iscommon to acute HF (AHF) that exhibits mild to moderate decrease incardiac contractility reserve.

In ADHF, which is characterized by worsening of the symptoms: typicallyshortness of breath (dyspnea), edema, and fatigue, in a patient withexisting heart disease, the cardiac filling pressures generally start toincrease more than 5 days preceding an admission. While this couldreflect a state of effective venous congestion following a build-up ofvolume, nearly 50% of patients gain only an insignificant amount ofweight (<1 kg) during the week before admission. This means that inabout 50% of cases, decompensated HF is not caused by externally addedfluid, but rather symptoms and signs of congestion can be entirelyexplained by redistribution of the existing intravascular volume.

Acute increases in sympathetic nervous tone due to a variety of knowntriggers like cardiac ischemia, arrhythmias, inflammatory activity andpsychogenic stress and other unknown triggers can disrupt the body'sbalance and lead to a fluid shift from the splanchnic venous reservoirinto the effective circulation. This results ultimately in an increasein preload and venous congestion. This explains the finding that in ADHFin both HFrEF and HFpEF was preceded by a significant increase indiastolic blood pressures.

In many patients with HFpEF relatively small increases in diastolicpressures/preload can result in decompensation due to impairedrelaxation of the ventricles. Thus patients with HFpEF are moresensitive to intrinsic or extrinsic fluid shifts.

Chronic CHF is characterized by longstanding venous congestion andincreased neurohumoral activation. Like in acute heart failure, thesplanchnic vascular bed has been identified as a major contributor to HFpathophysiology. Chronic decrease in vascular compliance and capacitancemakes the human body more susceptible to recurrent acutedecompensations, making significant the consequences of chroniccongestion of the splanchnic compartment. While the splanchnic vascularcompartment is well suited to accommodate acute fluid shifts (e.g.change of posture to orthostasis, exercise and dietary intake of water),the regulation of the splanchnic vascular bed becomes maladaptive inchronic disease states associated with increased total body volume andincreased splanchnic vascular pressure.

Clinically observed effects of HF drug regimens like nitroglycerin andACE inhibitors exhibit their positive effects in the treatment of HF inpart through an increase in splanchnic capacitance subsequently shiftingblood into the venous reservoir thereby lowering left ventriculardiastolic pressure.

An orthostatic stress test (tilt test) can help to distinguish lowvascular capacitance from normal. Orthostatic stress causes blood shiftsfrom the stressed volume into the unstressed volume. Veins of theextremities are less compliant than splanchnic veins, and therefore,their role as blood volume reservoir is relatively minimal. Less knownis that during body tilt or standing up blood goes mostly into thesplanchnic compartment, which results in a decreased preload to theright and left heart. Stimulation of the atrial and carotidbaroreceptors results in an increased sympathetic tone causingsplanchnic vasoconstriction. This compensatory mechanism is important,as it can rapidly shift volume from the unstressed compartment intoactive circulation. The hemodynamic response to tilt in chronic HF isatypical, as there is no significant peripheral pooling in the uprightposture. It is assumed that the reduced capacitance of the splanchniccompartment serves as a marker of sympathetic tone to the splanchnicvasculature.

Acute oral or intravenous fluid challenge can also serve as a test ofsplanchnic vascular capacitance. The vascular capacitance determines how“full” the unstressed volume reservoir (venous reservoir) is and howmuch more fluid can be taken up to it in order to buffer the increase ineffective circulation (stressed volume). A fluid challenge could testthe capacitance by measuring the effects of a fluid bolus given via anI.V. infusion on cardiac filling pressures.

Patients with a “full tank”, (low capacitance of venous reservoir), willnot be able to buffer the hemodynamic effects of the fluid bolus as wellas patients with a high capacitance in the venous reservoir. This willmanifest in a bigger blood pressure increase for the same added volume.Thus patients with HF, HFpEF and patients with increased SNA will bemore likely to respond to the fluid challenge with a disproportionalrise in cardiac filling pressures. This could serve as a patientselection tool as well as measure of therapeutic success.

To target the splanchnic nerves, primarily the greater splanchnic nerve(GSN) and the thoracic sympathetic trunk and celiac plexus, severalinvasive and minimally-invasive methods can be used. Although notlimited to these methods, access can be transthoracic, transabdominal,percutaneous, transvascular or transvenous. Transvascular accessutilizes both vessels of the venous and arterial system, while atransvenous method accesses the nerve structures through the venousnetwork of the cardiovascular system and is envisioned in at least thefollowing vessels: azygos/hemiazygos vein, intercostal veins, vena cava,adrenal vein, phrenic vein, and portal vein.

Tools for catheter navigation include use of extravascular landmarkssuch as intercostal space and/or vertebrae. Internal scans or detectionmethods may include fluoroscopic detection of radiographic landmarks, CTscans, MRI and/or ultrasound. These scans would be used for direct nervevisualization, or visualization of adjacent vascular (e.g. azygos) andnon-vascular structures (diaphragm, vertebrae, ribs). The use ofradiocontrast and a guide wire can aid in the placement of the ablationelement of the device.

At the targeted site, some proposed methods of target modulation,specifically to ablate a target nerve include cryo or high temperaturebased ablation, local drug delivery (e.g. local injection andinfiltration by neurolitics, sympatholytics, neurotoxins), localanesthetics, or energy delivery that could include radio frequency (RF)ablation, ultrasound energy delivery, or mechanical compression.

In light of the foregoing, it is desired that the present inventionprovide treatment that is used in the cardiac catheterization laboratoryto ablate a splanchnic nerve such as a greater splanchnic nerveunilaterally on the right or left side of the body or bilaterally onboth sides to mobilize blood out of the effective circulation (stressedvolume) and shift it into splanchnic organs or vasculature, andsplanchnic vascular bed (venous reservoir) in order to moderatelydecrease and normalize cardiac preload, reduce venous congestion,relieve pulmonary congestion, reduce pulmonary blood pressures and thussensation of dyspnea and to increase or relatively maintain strokevolume, enhance blood circulation and improve overall heart function. Assuch, use of the present invention would grant patients suffering fromheart disease a return to a higher quality of living and may preventhospital admissions with ADHF.

Further, the present invention could be used in the therapy of acute aswell as chronic HF decompensation. Acute HF decompensation would beprevented or its progression halted by an offloading of the stressedvolume and relieving venous congestion, which is the main component ofthe renal dysfunction in HF. The invention can be used in support oftraditional medical therapy like diuretics as it can interrupt or delayprogression of cardiac decompensation. Said offloading of the stressedvolume and relieving venous congestion can be expected to increasediuretic responsiveness of the patients.

In a chronic CHF state, the invention can be used on a long-term basisto improve fluid distribution, increase capacitance, relieve venouscongestion, improve relaxation of ventricles and thus improve symptomsof congestion like shortness of breath and improve exercise capacity.

Compared to present methods of nerve ablation, the invention aims tocreate a reliable and consistent method of targeted selective GSNablation that is safe and causes no adverse effects such as pain,serious long term damage to gastric function, sensation or otherunintended, untargeted nerve damage.

Additionally, the present invention fulfills a long desired need toprovide a treatment for HF, especially for patients of diastolic orHFpEF and particularly a need to reduce pulmonary artery blood pressureand relieve dyspnea (shortness of breath) in response to exercise and insome cases at rest.

BRIEF DESCRIPTION OF THE DRAWINGS

Other advantages of this invention are made apparent in the followingdescriptions taken in conjunction with the provided drawings wherein areset forth, by way of illustration and example, certain exemplaryembodiments of the present invention wherein:

FIG. 1 is an anatomical representation of the supply of sympatheticnerve fibers to organs of the human body.

FIG. 2 is a flow diagram showing the mechanisms of decompensated heartfailure

FIG. 3 is a partial flow diagram showing the role of splanchniccompartment in blood volume distribution in heart failure.

FIG. 4 is a partial flow diagram showing the role of the therapeuticeffects of invention to heart failure.

FIG. 5 is a graphical representation of pathophysiology of acutedecompensated heart failure.

FIG. 6 is an anatomical representation showing azygos veincatheterization for right GSN ablation with an intravenous cathetersuitable for stimulation and ablation.

FIG. 7 is an anatomical representation showing the azygos veincatheterization for left GSN ablation with an intravenous cathetersuitable for stimulation and ablation.

FIG. 8 is an anatomical representation showing the hemiazygos veincatheterization for left GSN ablation with an intravenous cathetersuitable for stimulation and ablation.

FIG. 9 is an anatomical representation showing the hemiazygos veincatheterization for right GSN ablation with an intravenous cathetersuitable for stimulation and ablation.

FIG. 10 is an anatomical representation showing left GSN catheterizationvia the azygos vein to posterior intercostal vein.

FIG. 11 is an anatomical representation showing the azygous vein andgreater splanchnic nerve and their proximity, which allows for atransvenous approach with an intravenous catheter deployable structuresuitable for stimulation and ablation.

FIG. 12 is a plot of aortic and ventricular pressure in response toelectrical stimulation of a GSN in an animal study.

FIG. 13 shows a catheter suitable for stimulation and ablation deployedin an intercostal vein in close proximity to the GSN and sympatheticchain.

FIGS. 14A and 14B illustrate the different physiological responsesbetween stimulation of the sympathetic chain (FIG. 14A) versusstimulation of the GSN (FIG. 14B).

FIG. 15 is a mapping algorithm used to determine an optimal electrodepair that is based on in Mean Arterial Pressure (MAP) levels recordedafter a stimulus is delivered.

FIG. 16 is a plot of mean arterial pressure over time showing responseto stimulation of an ablated nerve.

FIG. 17 is a flowchart illustrating the steps from patient selection toablation therapy.

FIG. 18 is a schematic illustration of a distal end of an ablationcatheter.

FIGS. 19A to 19D are graphs illustrating responses of the patient to theblocking of a nerve.

DETAILED DESCRIPTION

The present invention relates to a medical device and method that offerstreatment of heart disease, dysfunction and heart failure, particularlyHFpEF through the mechanism of increased venous capacitance and reliefof pulmonary congestion and increased diuretic responsiveness. Thistreatment is provided through ablation of at least a portion of asplanchnic nerve (e.g., greater splanchnic nerve or lesser splanchnicnerve) with a catheter delivered to a vessel (e.g. azygos or hemiazygosvein or intercostal vein) to impede or stop communication of a nervesignal along the ablated nerve, which can affect physiological responsesthat are directly or indirectly involved in the numerous factors ofcardiovascular health.

One preferred embodiment comprises a catheter delivered through apatient's vascular system to an azygos or hemiazygos vein and theirbranches for ablating a portion of a right or left greater splanchnicnerve. The catheter may comprise an ablation element (e.g., RFelectrodes, cryogenic applicator, chemical agent delivery needle,ultrasound transducer, laser emitter), and a means to confirm proximityto target nerve, such as a greater splanchnic nerve, or non-targetneural structures (e.g., electrical stimulation or blocking electrodes,cryogenic applicator, chemical agent delivery needle, visual aids suchas radiopaque or echogenic markers). The catheter may be used as part ofa system comprising other components that contribute to the function ofthe catheter. For example, the system may comprise an ablation energysource (e.g., RF signal generator, cryo console, ultrasound signalgenerator, chemical agent source or pump, laser generator), acontroller, or a computerized user interface. To ablate a portion of atarget nerve, the ablation energy source delivers ablation energy froman ablation element positioned in a patient's blood vessel (e.g. azygos,intercostal or hemiazygos vein) proximate the target nerve. The ablationenergy passes from the ablation element to the target nerve. To confirmproximity to a target or non-target neural structures a stimulatingagent, such as electric field or a drug known to activate sympatheticnerves, may be delivered to temporarily activate or block nerve activityand a physiological response may be observed or monitored forcorrelation to the nerve stimulation or block. Similarly, success ofablation may be confirmed by electric stimulation of the target nerveand observing the physiologic response, changes in the physiologicresponse compared to pre-ablation or absence of physiologic responsewhere one is expected. Physiology

FIG. 1 is an anatomical representation of the supply of sympatheticnerve fibers to organs of the human body. The SNS is part of theautonomic nervous system, which also includes the parasympatheticnervous system.

The SNS activates what is often termed the fight or flight response.Like other parts of the nervous system, the sympathetic nervous systemoperates through a series of interconnected neurons. Sympathetic neuronsare frequently considered part of the peripheral nervous system,although there are many that lie within the central nervous system.

Sympathetic neurons of the spinal cord (which is part of the CNS)communicate with peripheral sympathetic neurons via a series ofsympathetic ganglia. Within the ganglia, spinal cord sympathetic neuronsjoin peripheral sympathetic neurons through chemical synapses. Spinalcord sympathetic neurons are therefore called presynaptic (orpreganglionic) neurons, while peripheral sympathetic neurons are calledpostsynaptic (or postganglionic) neurons.

At synapses within the sympathetic ganglia, preganglionic sympatheticneurons release acetylcholine, a chemical messenger that binds andactivates nicotinic acetylcholine receptors on postganglionic neurons.In response to this stimulus, postganglionic neurons principally releasenoradrenaline (norepinephrine). Prolonged activation can elicit therelease of adrenaline from the adrenal medulla.

Once released, noradrenaline and adrenaline bind adrenergic receptors onperipheral tissues. Binding to adrenergic receptors causes the effectsseen during the fight-or-flight response. These include pupil dilation,increased sweating, increased heart rate, and increased blood pressure.

Sympathetic nerves originate inside the vertebral column, toward themiddle of the spinal cord in the intermediolateral cell column (orlateral horn), beginning at the first thoracic segment of the spinalcord and are thought to extend to the second or third lumbar segments.Because its cells begin in the thoracic and lumbar regions of the spinalcord, the SNS is said to have a thoracolumbar outflow. Thoracicsplanchnic nerves (e.g., greater, lesser, or least splanchnic nerves),which synapse in the prevertebral ganglia are of particular interest forthis invention.

FIG. 2 is a flow diagram showing the mechanisms of decompensated heartfailure. It illustrates the role of sympathetic nerve activation in themobilization of venous reservoir into the effective circulatory volumeleading to decompensation. Reversing, at least partially, by ablation ofa greater splanchnic nerve, the sympathetic activation of splanchnicnerves is expected to relieve HF symptoms and reduce load on the failingheart.

A particular area of interest in the body is the splanchnic compartment,splanchnic vascular bed, or splanchnic reservoir, which include thevasculature of the visceral organs including the liver, spleen, smalland large bowel, stomach as well as the pancreas. The splanchnic venousvascular bed serves as the major blood reservoir and can be affected byactivation (e.g., stimulation) or deactivation (e.g., blocking orablation) of splanchnic nerves and particularly of the greatersplanchnic nerve (GSN) causing mobilization, release or uptake of venousblood from or to splanchnic vascular beds, respectively, and importantchanges in circulating blood volume.

The GSN may at least partially control splanchnic venous capacitance.Capacitance is reduced in CHF patients and particularly in some veryhard to treat HFpEF patients as a part of overall elevated sympatheticstate. The sympathetic fibers in the greater splanchnic nerve bundlethat control contraction of splanchnic veins are the particular targetof the proposed ablation therapy. In the context of this invention theGSN can mean right or left greater splanchnic nerve and transvenousablation and stimulation can be performed from the azygos vein to accessthe right greater splanchnic nerve, or from the hemiazygos vein toaccess the left greater splanchnic nerve, or from their respectivetributaries (e.g. right or left intercostal veins) or a bilateraltreatment can be performed from both the azygos and hemiazygos to accessboth right and left greater splanchnic nerves.

The splanchnic congestion and high venous pressure is believed toadversely affect renal function and as illustrated by hepatorenalsyndrome that causes diuretic resistance. It is believed by inventorsthat the proposed ablation may reverse this phenomenon, improve renalfunction and enable diuretics to work (restore diuretic responsiveness).

FIG. 3 and FIG. 4 show some of the interactions between increases insympathetic nervous system activity, including natural firing of theGSN, and the storage of blood in the splanchnic bed. As illustrated byFIG. 3, increased central SNA, can manifest, at least partially, in theelevated activity of the GSN in all types of HF, resulting in a lowersplanchnic capacitance and possibly stiffened, less-compliant splanchnicbed and regional effects including a decrease in the amount of bloodstored in the splanchnic veins perfusing and surrounding the splanchnicorgans (e.g., liver, spleen, pancreas, stomach, bowels) and an increasein the amount of blood in central veins. The volume of blood insplanchnic veins or the splanchnic vascular bed can be described as a“venous reservoir”, or “unstressed volume” and refers to the bloodvolume that does not contribute to the effective circulating volume andis therefore hidden from circulation or the hemodynamically hidden bloodvolume. The volume of blood in central veins can be termed “effectivecirculatory volume” or “stressed volume” and refers to blood that ispresent mainly in the non-splanchnic veins and is one of the maindeterminants of preload to the heart and in CHF can contribute to venouscongestion, high pulmonary circulation pressures and sensation ofdyspnea.

Conversely, as illustrated by FIG. 4 the compliance of the splanchnicbed can be relaxed or normalized from the “stiff” of contracted state bydecreased sympathetic nervous system activity. Ablating a splanchnicnerve (e.g. GSN, lesser splanchnic nerve, least splanchnic nerve) canresult in a decrease of efferent sympathetic tone to smooth muscle inthe walls of veins in the splanchnic vascular bed referred to assplanchnic “venodilation” or in the overall decrease in sympatheticnervous system activity. Understanding and utilizing these interactionsare some of the primary aims of several of the exemplary embodiments ofthe present invention. Specifically, the capacitance of splanchnicvasculature is desired to be increased.

FIG. 5 shows one possible clinical scenario in which the sympathetichyperactivity of the greater splanchnic nerve leads to the accelerationof fluid overload and pulmonary venous congestion in an HFpEF patient.

Endovascular Ablation

Endovascular nerve ablation, or ablation of neural structures using acatheter delivered through a blood vessel, particularly deep visceralnerves that are near the blood vessel (e.g., less than about 5 mm froman internal vessel wall), may be advantageous over surgical resection orablation. For example, endovascular ablation may be less invasive, befaster procedurally, and have faster patient recovery. It may bebeneficial to use a patient's venous system to deliver ablation energysince interventions in veins are considered safer than in arteries.Blood pressure in a vein is lower and limits risk of bleeding and debrisor clot from ablation is safer since veins terminate in the lungs thatact as a natural blood filter. It is also advantageous that veins aremore elastic and can be occluded and stretched in order to achievebetter fixation and apposition of the ablating device in relation to thenerve. Specifically, in the case of an azygos or hemiazygos vein thereis large redundancy in the venous system and occlusion of the azygosvein is not dangerous to the patient.

There are several accepted methods of ablating a nerve through a wall ofa blood vessel such as RF ablation using resistive heating,cryo-ablation using cold, ultrasound heating ablation, and injection ofneurolytic blocking agent (e.g., form of nerve block involving thedeliberate injury of a nerve by the application of chemicals, in whichcase the procedure is called “neurolysis”) in which chemicals such asalcohol or more specifically acting sympatholytic agents likeguanethidine, botox (i.e., botulinum toxin A) and others can beapplicable.

A method and device for ablating a greater splanchnic nerve using anablation catheter placed in an azygos vein may be configured to safelyavoid important non-target nerves and structures. For example, theceliac ganglion is near the greater splanchnic nerve. Placement of anablation element that creates, for example, a 5 mm diameter lesion thatpermanently destroys the GSN where it is in close proximity of theazygos vein at or slightly above the diaphragm will protect the celiacganglion from ablation. Celiac ganglia are located in the abdominalcavity just below the diaphragm. Other non-target nerves may includelesser and least splanchnic nerves. Thus a targeted selective ablationof nerves is possible to suite needs of different groups of patientswith HF.

FIG. 6 shows an example of a catheterization approach from a leftsubclavian vein to a suitable position in an azygos vein for right GSNablation. FIG. 7 shows an example of a catheterization approach from theleft subclavian vein to a suitable position in a hemiazygos vein forleft GSN ablation by crossing over from azygos to hemiazygos vein.Endovascular approaches to the azygos vein may comprise introductioninto the vascular system, for example, at the radial, brachial,subclavian, jugular or femoral veins.

A guidewire may facilitate advancement of a catheter 10 through tortuousvessel pathways. The catheter may include an extended tubular member 12including lumens, such as for the guidewire for injection of drugs andradiocontrast. Both bilateral and unilateral, left and right GSNablation is possible and may be desired based on the patient's anatomyand responses to diagnostic stimulation.

Approaches to identify the best location (mapping) and target as well asthe best approach to GSN ablation are shown in FIGS. 8 and 9. Thesefigures show examples of a catheterization approach from a leftsubclavian vein to a suitable position in a hemiazygos vein for left andright GSN ablation, respectively.

The catheters in FIGS. 6 to 10 may each comprise at least one ablationelement 14, 22 to deliver ablation therapy as well as at least oneelectrical stimulation element to confirm proximity to a target nerve,such as a GSN, or non-target neural structures. The catheter in each ofFIGS. 6 to 10 may be used as part of a system comprising othercomponents that contribute to the function of the catheter. The systemmay comprise an ablation energy source 16 (e.g, RF signal generator,cryo console, ultrasound signal generator, chemical agent source orpump, laser generator), an electrical stimulation energy source and acomputer controller 18 with embedded logic and software and a userinterface with manual controls and displays. A console 20 may house theablation energy source, the electrical stimulation energy source, thecomputer controller, user interface and displays.

In an embodiment of the invention, as shown in FIG. 10, ablation andstimulation elements on a catheter are positioned in an intercostal veinnear a GSN and sympathetic chain. The ablation and stimulation elementscan be electrodes.

The catheterization approach used in this example is the one from a leftsubclavian vein via the azygous vein into the posterior intercostalvein. Other approaches are possible through suitable veins. The cathetermay comprise at least one ablation element to deliver ablation therapyand at least one electrical stimulation element to confirm proximity toa target nerve, such as a GSN, or non-target neural structures. Thecatheter may be used as part of a system comprising other componentsthat contribute to the function of the catheter. The system may comprisean ablation energy source, an electrical stimulation controller, or auser interface. Additional elements such as monitoring of temperatureand impedance of tissue can be added to improve performance and safetyof the ablation system.

In an embodiment of the invention, as illustrated in FIG. 11, anablation element on a catheter is positioned in an azygos vein near agreater splanchnic nerve. The catheter may comprise a deployablestructure positioned at its distal region. The deployable structurecomprises at least one ablation element (e.g., RF electrode) that isplaced in apposition with the azygos or hemiazygos vein wall when thedeployable structure is expanded. The deployable structure may be aballoon, a cage, a basket, a preformed shape such as a lasso or loop.The deployable structure may further comprise at least one stimulationelement 24 (e.g., electrical stimulation cathode and optionally anode),or a visualization aid (e.g., radiopaque marker, contrast deliverylumen). The azygos (and hemiazygos) veins which run up the right andleft sides of the thoracic vertebral column drain towards the superiorvena cava, in part within the thoracic cavity. Intravenous access viathe azygos vein allows for the catheter to access an area in proximityto the thoracic splanchnic nerves, in particular, the greater splanchnicnerve (GSN).

Experiments in animals and human cadavers where performed in which theGSN was successfully accessed with a catheter advanced to an azygos veinat the level of the diaphragm wherein an electrode was positioned closeenough to electrically stimulate and potentially ablate the greatersplanchnic nerve. In animals experiments GSN access was performed on theright side. This was confirmed by observing hemodynamic effects ofgreater splanchnic nerve stimulation with electric pulses applied fromthe azygos vein. Inventors also performed experiments where the GSN wassurgically accessed, visualized, stimulated with a nerve cuff and laterresected. Consistent and similar hemodynamic effects that suggestedtherapeutic possibilities were observed.

Stimulation Confirmation Embodiments

Regardless of the modality of ablation, embodiments of a device andmethod may further be configured to assist the ablation procedure with ameans to confirm safety and efficacy prior to and following an ablationstep. A means to confirm safety may comprise detection of a non-targetnerve or structure or absence thereof within a range of ablation energydelivery. A means to confirm technical efficacy may comprise detectionof a target nerve within range of ablation energy delivery before anablation step and absence of a target nerve signal transmissionfollowing the ablation step. A means to confirm procedural efficacy maycomprise temporarily blocking a target nerve to assess if a resultingphysiologic response is representative of a desired clinical effect ofthe procedure.

To facilitate a technically effective procedure, an embodiment mayinvolve confirming that the ablation lesion will be created in a desiredlocation and that a targeted nerve is sufficiently within range ofablation energy delivery before ablation energy is delivered to causeirreversible damage to the target nerve or potentially to an untargetedarea. This may be achieved by delivering an electrical stimulatingsignal from at least one stimulating electrode to excite nerves inproximity to the stimulating electrode and observing a physiologiceffect such as hemodynamic changes. The stimulating electrodes may be apair of electrodes constituting an anode and cathode, a single monopolarelectrode communicating with a dispersive electrode, the same componentthat is used to deliver an electrical ablation energy such asradiofrequency or electroporation, or a distinct electrode or pair ofelectrodes positioned appropriately relative to an ablation element.

FIG. 12 illustrates a response to stimulation of a GSN at the level justabove the diaphragm in an animal experiment performed by the inventors.The recognizable waveforms of aortic and left ventricular pressurereflect the physiologic response to stimulus. Similar increases wereobserved in central venous pressure, right atrial pressure and pulmonaryartery pressure that can be measured and monitored in real time in anywell-equipped modern catheterization laboratory by a trainedcardiologist.

In an embodiment wherein a stimulation electrode or pair of electrodesis distinct from an ablation element they may be positioned on thecatheter relative to one another so that the stimulation zone (e.g.,region in which the stimulation signal delivered by the stimulationelectrode is strong enough to elicit an action potential in a nerve)correlates with an ablation zone (e.g., region in which ablation energydelivered by the ablation element is sufficient to cause irreversible orlong lasting damage to nerve tissue).

A stimulation signal may be controlled by a computerized console 20 (SeeFIG. 6-10) and may comprise a signal profile that facilitatesconfirmation of technically efficacious positioning. The computerizedconsole may include processors accessing non-transitory memory storinginstructions that cause the console to generate a stimulation signal.For example, the size of a stimulation zone may be a function ofamplitude and a signal profile. The console may achieve the stimulationzone by delivering signal energy by varying amplitude (e.g., linearramp, stepwise ramp, alternating levels) or frequency of stimulation. Anobserved response corresponding to a given amplitude may indicatedistance of a target nerve to an ablation element, and delivery ofablation energy may be adjusted (e.g., manually or automatically) tocreate an efficacious ablation zone.

For example a different energy delivery electrode can be selected or thecatheter can be repositioned. In another example, a signal profilecomprises periods of on and off (e.g., stimulating amplitude(s) andnon-stimulating energy levels) in which a physiologic response mayfollow the signal profile to eliminate false positive or negativeassessments.

In an embodiment, a transvenous application of electrical stimulation ofa nerve delivering currents of 0.5 to 15 mA, frequency of 1 to 50 Hz andpulse duration of 50 to 500 microseconds may be suitable to test ifproximity to the nerve is within about 5 mm. Sedation may be used inorder to prevent painful sensation by the patient. If a physiologicresponse is elicited, the cathode electrode is very likely to be within1 to 5 mm distance from the target nerve and ablation in that area islikely to destroy the nerve permanently while sparing nerves outside ofthe ablation zone in embodiments configured to create an ablation zoneof about 5 mm. It is estimated that the location closest to the nerveand the corresponding electrode (See FIG. 13) will elicit response atthe lowest energy (example of nerve mapping). For example, the ablationelement may be an RF electrode (e.g., having an exposed surface area ofabout 5 to 15 mm3) in monopolar configuration with a dispersivegrounding pad on the patient's skin to complete the electrical circuit.

Ablation energy may be radiofrequency electrical current having afrequency in a range of about 350 to 500 kHz and a power in a range ofabout 5 to 50 W.

The delivery of RF energy may be controlled by an energy delivery moduleassociated with the computer console that uses temperature feedback froma sensor associated with the RF electrode. Observation of a physiologicresponse may involve equipment for measuring the response (e.g.,equipment known in the art for measuring or monitoring hemodynamicparameters such as blood pressure and heart rate, or with sensorsassociated with the catheter or the system) that provides an indicationof the parameter.

Confirmation of efficacious positioning may be assessed manually by apractitioner by observing the parameter measurements in real time.Alternatively confirmation may be assessed automatically by thecomputerized system console that takes input from the physiologicmonitoring equipment and compares it to a stimulation signal profile(automated mapping). The automated mapping or confirmation assessmentmay further select or assist in selecting an appropriate ablation energydelivery profile.

A catheter may be configured to monitor a physiologic response to nervestimulation and comprises a blood pressure transducer on the catheterthat may be positioned in a blood vessel in addition to an ablationelement and a stimulation element. The device or system may furthercomprise a second blood pressure transducer that may be positioned in adifferent part of the circulation system (e.g., arterial system such asfemoral or radial artery, pulmonary circulation such as pulmonaryartery, central venous system such as vena cava or right atrium of theheart or splanchnic circulation or pulmonary circulation system such asin a pulmonary artery) to compare blood pressure measured in differentlocations and assess changes in response to nerve stimulation.

To facilitate a safe procedure, an embodiment may involve confirmingthat the ablation lesion will not do irreversible damage to importantnon-target nerves, such as celiac ganglia or lesser splanchnic nerve, ifthat is the selected therapy modality, before ablation energy isdelivered. This may be achieved by electrically stimulating the adjacentnerves with the same or different electrodes and observing thephysiologic (e.g. heart rate or hemodynamic such as blood pressure orflow) effects. An embodiment may utilize the same principles andcomponents as described above wherein a stimulation zone is correlatedto an ablation zone however an observed physiologic response may beindicative that an important non-target nerve is stimulated. Anundesired response may occur instead of or as well as a physiologicresponse from stimulating a target nerve. In either case, a responsefrom an important non-target nerve may indicate that it is unsafe toablate as positioned. For example, an increase of central venouspressure (CVP) or pulmonary artery pressure (PAP) can indicate thedesired response in combination with the reduction of Heart Rate (HR);however, a concomitant increase in HR may indicate that an importantnon-target nerve is within the stimulation zone and associated ablationzone (e.g. nerve stimulating an adrenal gland) and the ablation elementand the associated stimulation element may be repositioned andconfirmation of safety and efficacy may be reapplied. If both a targetnerve and important non-target nerve are stimulated by the samestimulation signal then the nerves may be quite close together anddelivering ablation energy may be unsafe. To avoid risk of injuring thenon-target nerve the ablation element and stimulation element may bemoved and stimulation repeated until a position is found that is bothsafe and effective. For example, the catheter can be advanced ordifferent electrodes selected on the catheter placed along the azygos,hemiazygos or intercostal vein traveling along, crossing or traversingGSN and sympathetic chain (See FIG. 13). Alternatively, a catheter maycomprise multiple ablation elements and corresponding stimulationelements positioned along a length (e.g., about 1 to 5 cm) of a distalsegment of the catheter and stimulation regimens may be delivered toselect a position among the multiple positions that is optimal.

Alternatively, a stimulation signal profile may narrow the stimulationzone to identify an appropriate ablation setting that would ablate thetarget nerve and not the non-target nerve. In another embodiment acatheter may comprise a stimulation element (e.g., at least oneelectrode or an electrode pair or pairs) having a stimulation zone thatspatially corresponds with an ablation zone, and additionally have atleast a second stimulation element that is far enough away from theablation element(s) that the second stimulation zone corresponds to aregion that is beyond the ablation zone. In this embodiment aphysiologic response elicited by the second stimulation element and notthe stimulation element associated with the ablation element mayindicate safe positioning. In an embodiment wherein the ablation elementis a cryo-ablation element, a cryo- mapping technique may be applied tocool the area and temporarily impede nerve conduction withoutpermanently destroying the nerves. For example, the cryo- mappingtechnique may comprise delivering cryogenic energy from the cryo-ablation element but with a duration or temperature that onlytemporarily impedes nerve conduction. A physiologic response of a targetnerve or non-target nerve to temporarily impeded nerve conduction may bedifferent than a stimulated nerve. A temporarily impeded target nervemay have a similar response as an ablated target nerve but with a shortduration.

FIG. 13 is an illustration of an endovascular catheter 30 includingmultiple ablation and stimulation elements 32. The catheter ispositioned in an intercostal vein via an azygous vein. The ablation andstimulation elements 32 may be on the surface of the catheter andpositioned at regular increments along the length of a distal end regionof the catheter.

The distal segment of the catheter can be navigated into the azygos andintercostal vein space of thoracic vertebrae T9, T10 or T11 asillustrated by FIG. 10. The catheter is in close proximity to both theGSN and the sympathetic chain. The diameter of the catheter whereelectrodes are located can be 2-6 mm and almost occluding and evenpossibly distending the intercostal vein. The targeted nerve can beidentified by using electrical stimulation of the nerves along thecatheter using selected electrodes as cathodes and anodes and monitoringthe physiological responses.

FIG. 14A and 14B are plots of the different physiological responsesobserved during stimulation of the sympathetic chain and GSN in animals,respectively. In an animal study, the left sympathetic chain wasstimulated via a catheter positioned in the intercostal vein at the T6level. The HR and MAP increased during stimulation of the sympatheticchain as shown on FIG. 14A. The box illustrates time of application ofenergy between 60 and 90 seconds on X-axis. Changes in pulmonary arterypressure PAP and right atrial pressure RAP confirm that the preload ofthe heart increased in response to stimulation.

In a separate experiment the right GSN was selectively stimulated usinga cuff electrode placed on the thoracic section of the GSN. Results areillustrated by FIG. 14B. During the GSN stimulation period shown as abox, mean systolic pressure (MSP) measured in the femoral arteryincreased while the HR decreased. The reduction of HR was likely causedby the normal compensatory response of the arterial baroreflex when thesudden upregulation of heart stroke volume is detected. Inventorsconfirmed that while blood flow in the inferior vena cava increased,cardiac output remained relatively constant. The Ped trace on FIG. 14Billustrates the increase of left ventricular end diastolic pressure(LVEDP) in response to the mobilization of fluid from the venousreserve.

To facilitate a clinically effective procedure, an embodiment mayinvolve confirming that a patient will experience the desiredphysiologic effect of ablation before delivering ablation energy. Thismay be achieved by electrically, pharmacologically or cryogenicallyblocking the nerve temporarily and observing the physiologic response(e.g., hemodynamic effect). Optionally, vascular nerve mapping orconfirmation of technically efficacious positioning as described hereinto indicate that a target nerve is within an ablation zone orconfirmation of safe positioning to indicate that an importantnon-target nerve is not within the ablation zone may first be done, thena temporary nerve block may be performed to assess potential clinicalsuccess. If potential clinical success is assessed to have a physiologicresponse as desired then ablation energy may be delivered to produce apermanent or more long lasting clinical effect, which may be analogousto the temporary clinical effect. Conversely, if the physiologicresponse to temporary blocking is not as desired, a physician may decideto not proceed with ablation. A different set of stimulation andablation elements may be chosen to apply confirmation steps a differentposition may be found or the procedure may be aborted.

To facilitate a technically and clinically effective procedure, anembodiment may involve confirming that an ablation was successful andthat the target nerve no longer conducts signals following delivery ofablation energy. This may be achieved by delivering stimulation signalswith the same or different stimulation elements and observing thephysiologic (e.g. hemodynamic) effect.

Since the greater splanchnic nerve tracks along the azygos vein for aconsiderable length, (e.g., up to about 3 to 5 cm), it may be possibleto stimulate the greater splanchnic nerve distal to the ablation siteand observe the absence of the hemodynamic effect. A device configuredto stimulate distal to an ablation site may comprise a stimulationelement having a stimulation zone associated with an ablation zone andadditionally, a stimulation element positioned distal to the ablationelement a sufficient distance to be beyond the ablation zone.

An embodiment of a method for confirming that the relative position ofan ablation element to the target nerve (in this case a greatersplanchnic nerve) is safe and technically effective before deliveringablation energy or selecting the appropriate ablation element andcorresponding stimulation elements from a group of ablation andstimulation elements on a device may include the use of a mappingalgorithm.

The mapping algorithm, shown in FIG. 15 comprises the following steps:

-   -   (i) Select electrode pairs (ideally below T10 and above        diaphragm or along the selected intercostal vein within 1-3 cm        from azygos or hemiazygos branching). It is understood that        electrode pairs refer to bipolar stimulation and ablation and        one electrode may be selected if ablation or stimulation is        monopolar.    -   (ii) Record a selected hemodynamic parameter (e.g. MAP, CVP,        PAP, RAP) to establish the baseline. See, e.g., FIGS. 19A to 19D        before “GSN cut”.    -   (iii) Deliver Stimulation pulse with Current (I), pulse width        (pw), frequency (F) and duty cycle (D) in about I=0-10 mA,        pw=100-1000 us, F=20-40 Hz, D=50% for 20-60 s. On and at least        20-60 s OFF. (See FIG. 16).    -   (iv) Record a selected hemodynamic parameter or parameters (e.g.        HR, MAP, CVP, PAP, RAP) such as shown in FIGS. 19A to 19D after        GSN cut.    -   (v) If the selected hemodynamic parameter>20% from baseline        allow to return to baseline and possibly repeat.

Average measurements for 3 stimulations, for example, and if standarderror is within +/−10%, the change in the selected hemodynamic parametermay be considered to be relevant.

Another method of confirming a suitable location for the ablation andstimulation elements prior to delivering ablation energy comprises astimulation test in which a specific current, frequency and pulse widthare selected (e.g., manually or automatically by a computerizedalgorithm) and stimulation is performed between pairs of electrodes thatare in contact with the wall of the vessel (e.g., vein, azygos vein,hemiazygos vein). When the electric field is sufficient to activate theGSN, a rapid rise in Mean Arterial Pressure (MAP) or CVP or PAP andother hemodynamic changes occurs within a few seconds and can begraphically recorded and compared to assess ablation element placement.

A method of confirming technical success following delivery of ablationenergy, in other words confirming that a target nerve has successfullybeen ablated may comprise the same or similar electrical stimulationparameters delivered from the same stimulation electrodes followingablation. Alternatively or additionally electrical stimulation may bedelivered from stimulation electrodes positioned proximal to thelocation of an ablation (closer to the brain or sympathetic chain) wherea physiologic response was elicited prior to ablating. Absence ofresponses or significant attenuation of responses will indicatetechnical success of the ablation.

To confirm this notion FIG. 16 illustrates an experiment where thehemodynamic response to a greater splanchnic nerve stimulation and blockwith locally injected lidocaine, a nerve blocking agent, was tested inan animal. Time on the X-axis is in minutes. The Y-axis representsarterial blood pressure in mmHg. The first arrow from the left indicatesthe time of injection of lidocaine. The second arrow indicates the timeof application of electrical stimulation to the greater splanchnic nerveproximal to the blocked area of the nerve. The term “proximal” as usedherein with reference to a relative position on a nerve denotes alocation nearer to a point of origin, such as brain, spinal cord,sympathetic chain or a midline of the body and where the term “distal”is used to denote a location further away from the point of origin andcloser to the innervated peripheral organ such as splanchnic vascularbeds, liver and spleen. Following the first stimulation proximal to thenerve block, no or very little physiologic response is observed onarterial blood pressure, or other physiologic parameters that areomitted on this graph for simplicity. The third arrow illustrateselectrical stimulation of the greater splanchnic nerve for 30 secondsapplied distal to the lidocaine blocked area. The physiologic responsemanifests by increase of mean arterial blood pressure and otherhemodynamic parameters as described in this application. Thisexperiment, performed using surgery, can be replicated usingendovascular ablation with the use of appropriate tools and advancedimaging. Moving the stimulation electrode along the azygos vein, forexample, to points distal and proximal the ablation lesion can confirmthe effectiveness of ablation.

Alternatively switching between electrodes spaced along the length ofthe catheter (See FIG. 13 for example) can be used. A simple automationdevice can be envisioned to test different electrode pairs and measureresponses then creating a report on the user interface.

Fluoroscopic imaging using body landmarks such as vertebrae, heart,veins and the diaphragm can be used to facilitate positioning of anablation element or stimulation elements of a catheter. If the nervewere unsuccessfully ablated, which may be indicated by a positivehemodynamic change in response to stimulation of the greater splanchnicnerve proximal the ablation, then recourse may comprise ablationrepeated at a higher energy level, ablation repeated at a differentlocation, or improved electrode apposition.

It is noted that MAP monitoring as mentioned above is an example andhemodynamic monitoring does not necessarily need to be invasivemonitoring and may be accomplished with a less invasive monitoring ofblood pressure, for example using a Nexfin or ClearSight device(Edwards) for continuous monitoring of hemodynamics commonly used inhospitals. The ClearSight system quickly connects to the patient bywrapping an inflatable cuff around the finger. The ClearSight systemprovides noninvasive access to automatic, up-to-the-minute hemodynamicinformation including: SV, CO, SVR, or Continuous Blood Pressure (cBP).Such a monitoring device may be hooked up to a computerized console tocommunicate physiologic response to the computer, which may determinestimulation or ablation parameters based on the physiologic responses.

An embodiment of a system of the present invention may comprise anablation catheter having at least one ablation element (e.g., RFelectrode) and at least one associated stimulation element (e.g.,stimulation electrode), a computerized console configured to generateand control delivery of a stimulation signal to the stimulation element,and a computerized console configured to generate and control deliveryof an ablation signal (e.g., RF electrical current) to the ablationelement. The stimulation console and the ablation console may beseparate machines or integrated into one machine and may communicate toone another. The system may further comprise components necessary tosupport the type of ablation energy for example, if the ablation energyis RF electrical current the system may further comprise a dispersivegrounding pad; if the ablation energy is a chemical agent the system mayfurther comprise a means to inject the agent such as a manually operatedsyringe or automatically controlled pump. The system may furthercomprise a hemodynamic monitoring device that is in communication withthe stimulation console or ablation console to provide feedback ofhemodynamic response to stimulation or ablation. The computerizedconsoles may comprise algorithms that facilitate analysis of stimulationand hemodynamic response. For example, an algorithm may compute if ahemodynamic response to a stimulation is significant based on time ofresponse, repeatability, difference from baseline.

In embodiments wherein an ablation catheter comprises multiple ablationelements and associated stimulation elements, see FIGS. 13 and 18, analgorithm may facilitate selection of an optimal ablation element forexample, based on strongest or quickest response to stimulation, andthen deliver ablation energy to the selected ablation element. A consolemay comprise a graphical user interface that provides intuitive graphicsor messages that help a user understand analysis of stimulationresponse.

FIG. 17 is a chart that illustrates an example of patient flow frompatient selection to the execution of ablation of the GSN to treat heartfailure. One means for the selection of patients suitable for GSNablation may include evaluation of splanchnic vascular capacitance. Anorthostatic stress test (tilt table test), fluid challenge, exercisetest or an appropriate drug challenge can help distinguish low vascularcompliance from normal. Orthostatic stress causes blood shifts from thestressed volume to the unstressed volume. In healthy patients, tocompensate for the shift, sympathetic tone increases resulting insplanchnic vasoconstriction and rapid mobilization of blood from theunstressed compartment to the active circulation. The hemodynamicresponse to tilt in chronic CHF is atypical, as there is not significantperipheral pooling in the upright posture indicating diminishedsplanchnic vascular capacitance. Acute oral or intravenous fluidchallenge is another test to assess splanchnic vascular capacitance. Afluid challenge could test the capacitance by measuring the effects of afluid bolus on cardiac filling and pulmonary pressures. Patients withlow capacitance of the splanchnic venous reservoir will be unable tocompensate for the hemodynamic effect of the fluid bolus. Patients withHF, HFPEF and patients with increased SNA will be more likely to respondto the fluid challenge with a disproportional rise in cardiac filingpressure and other related and measurable physiologic parameters. Thisresponse would indicate that the patient might be a candidate for GSNablation therapy. After patient identification as a candidate forablation therapy, the process of identifying the appropriate nervetarget is implemented as the first step in the ablation procedure.Proper identification of the target nerve as well as non-target nervesor structures within the range of the ablative energy (mapping) isimportant to confirm the safety and efficacy of the ablation procedure.

FIGS. 13 and 14 illustrate a means for using differences inphysiological responses to electrical stimulation to identify targetnerve (GSN) and a nearby non-target or different target nerve(sympathetic chain). The choices of therapy can be made selectively bythe physician based on the mapping information and the patient'sindividual responses and needs. For example an HFpEF patient with highchronic HR or BP (hypertension) may require different targeting than onewith low blood pressure. After nerve target identification andselection, one optional means of confirmation of procedural efficacy isto temporarily block the nerve target and evaluate whether thephysiological response is consistent with the desired clinical effect.After nerve target identification has been confirmed, the non-targetnerves or other structures have been deemed outside of the range ofablation energy, and procedural efficacy has been confirmed; ablationtherapy may be initiated.

Confirmation of the technical efficacy or success of the ablationprocedure may be accomplished by delivering electrical stimulationproximal to the location of an ablation where a physiological responsewas elicited prior to ablation. Absence or attenuation of responses willindicate technical success of the ablation procedure (see FIG. 16).Another means of confirming technical efficacy may be evaluatingsplanchnic vascular capacitance (tilt table and/or fluid challenge) andcompare to results before the procedure. If the ablation procedure is asuccess, no further action is needed. If the procedure is notsuccessful, the clinician may opt to provide additional ablation therapyat the same site and/or repeat the procedure of identifying additionalnerve targets (e.g, bilateral ablation) and providing ablation therapyas described previously.

Ablation Catheter Embodiment

FIG. 18 schematically illustrates a distal end of a catheter comprisinga deployable balloon equipped with multiple surface electrodes capableof transvenous stimulation and RF ablation of a nerve from within ablood vessel. This device can be used in conjunction with hemodynamicmonitoring to locate the greater splanchnic nerve, confirm a suitablysafe and effective placement of ablation electrodes, ablate the greatersplanchnic nerve, and confirm technical success of the ablation prior towithdrawing the device from the body and closing the venous puncture. Inthis embodiment the catheter shaft connects to a deployable structuresuch as a balloon, which is shown placed in an azygos vein and possiblydistending the walls of the vein to bring ablation electrodes andstimulation electrodes in apposition with the walls of the vein.Application of a stimulation level current (energy) systematically fromstimulation electrodes positioned around the balloon and in contact withthe vein wall around its inner circumference while observing physiologicresponse may be done to identify where the greater splanchnic nerve islocated along the circumference of the vein. If the electric fieldgenerated by the stimulation current from the electrode elicits theexpected hemodynamic response, the longitudinally corresponding ablationelectrode can be used to apply an ablation level of energy to create alesion.

Application of stimulation current to the electrode following deliveryof ablation energy while observing physiologic response can be used toconfirm technical success, wherein absence or decrease of a physiologicresponse compared to the response observed prior to ablation mayindicate that the nerve was successfully ablated.

In one embodiment, the catheter may be delivered transvenously throughthe cardiovascular system, specifically to the azygos vein via femoralaccess or internal jugular vein (IJV) access. It is envisioned that theablation element may be positioned with or without the aid of a guidewire. When desired, a hollow, multi-pole catheter can be used tomaintain natural flow levels within a blood vessel.

Stimulation elements used for confirmation of ablation element'sposition or confirmation of technical or clinical success are envisionedto contain one, two or more electrodes arranged in series or arrays,distributed and spaced circumferentially or longitudinally, which arechosen selectively to provide a sufficient, optimal, or a situationalamount of electrical signaling. In these embodiments, the stimulationelement may also have a plurality of electrodes that may be usedinitially to map a suitable location in an azygos or other suitable veinwhere the greater splanchnic nerve runs within close proximity for thelength of 1-5 cm at a distance of about 1-5 millimeters, or crosses thevein, sometimes about 2-3 millimeters from the vein wall, throughdetecting a specific hemodynamic response to stimulation.

By way of example, the catheter and console system may comprise acatheter 10 having multiple electrodes spaced along a flexible shafthaving a distal end region configured to be placed in an intercostalvein of a patient. The console is configured to generate and controldelivery of ablation signals (high energy electrical pulses) andelectrical stimulation signals (low energy electrical pulses). The lowenergy signals may include frequencies in the range of 5-50 Hz and highenergy signals include frequencies in the range of 400-500 Hz. The lowenergy signal is selected to stimulate nerves proximate to the activeelectrode and the high energy signal is configured to ablate the nervesproximate to the active electrode. The signals are applied to theelectrodes on the distal end region of the catheter. The console iscapable of selectively applying low and high levels of energy to eachthe electrodes, such as by sequentially applying low energy pulses toall of the electrodes and applying high energy pulses to selected onesof the electrodes.

The console may be configured with a controller configured, e.g.,programmed, to select and thereby activate an electrode and or group ofelectrodes (monopolar and/or bipolar) and; to select delivery of high orlow energy. The selection means for selecting electrode and delivery caninclude a switch or program logic. The console may include physiologicmonitoring device or devices in communication with the console, wherethe physiological monitoring device may include sensors located on thecatheter device, elsewhere within the patient vasculature, and/ornon-invasively.

A computer controller in the console may execute software and logic thatinclude algorithms that facilitate analysis of hemodynamic andphysiologic values recorded from patient monitoring device or devices incommunication with the console. Examples of hemodynamic andphysiological parameters are pupil dilation, increased sweating,increased heart rate, increased blood pressure, increased mean arterialpressure and any combination thereof.

The algorithms may confirm the positioning of the electrodes along thecatheter in the intercostal vein with respect to the target nerve byautomatically detecting a change in at least one selected hemodynamic orphysiological parameter which occurs in response to the activation of anelectrode on the catheter by a stimulation pulse. The algorithm mayinitially cause the recordation of a baseline vale of the hemodynamicparameter. Thereafter, algorithm causes stimulation pulse to be appliedto the intercostal vein by one or more of the electrodes on thecatheter. The stimulation pulse may have a current (I), a pulse width(pw), a frequency (F) and a duty cycle (D) wherein I=0-10 mA,pw=100-1000 us, F=20-40 Hz, and D=50% pulsing between 20-60 s. As eachstimulation pulse is applied, the algorithm records the value of theselected hemodynamic or physiological parameter. The application of astimulation pulse and recording the parameter value resulting from thepulse may proceed in a sequence for each of the electrodes on thecatheter.

The recorded parameter values are used to select the electrodes are toreceive an ablation pulse. The selection may be the electrode(s)corresponding to the largest change in the parameter value from thebaseline value. Further, the selection may be to identify electrodeswhich, which applying the stimulation pulse, caused the parameter valueto exceed a certain threshold, such as a twenty percent change (20%)from the baseline value.

To ensure a reliable parameter value, the stimulation pulse may beapplied several times, such as three by each of the electrodes. Theparameter value is recorded during each stimulation pulse. The averageof the parameter values for each of the stimulation pulse applied to aspecific electrode may be used as the parameter value to select anelectrode for the ablation pulse. Also, a check may be made to theparameter values to conform that are within a certain range, such aswithin ten percent of each other. If any of the values are outside ofthe range, additional stimulation pulses may be applied to determine theaverage value or an alert may be generated by the console that is givento the health care provider.

The algorithm followed by the computer controller may be used to confirma patient will experience the desired physiological effect of ablationbefore delivering ablation therapy is performed by an automatedalgorithmic process. Such an algorithm may include: temporarily blockingthe target nerve with a stimulation signal, recording the physiologicresponse while the nerve is blocked, and evaluating the physiologicresponse to determine if the patient should undergo ablation of nerve byablating the intercostal vein near the nerve. Clinical effectiveness isdetermined by comparing the recorded response to the desired physiologicresponse. The desired response may be progressive reductions inpressures (e.g., MAP, PAP, and LVEDP).The target nerve may also betemporarily blocked pharmacologically or cryogenically. If temporaryblocking does not achieve the desired effect, the physician may decidenot to proceed with ablation, select a different electrode configurationon the catheter to apply a stimulation signal and thereafter an ablationsignal, or move rotationally or laterally the catheter and itselectrodes in the intercostal vein.

The algorithm executed by the computer controller may also confirm thetechnical efficacy or success of the ablation procedure. Theconfirmation steps would be after (post) the ablation of the nerve viathe intercostal vein. The conformation steps may include electricalstimulation by the catheter to a region of the intercostal vein the sameas or proximal to the location of the ablation. The patient's response(physiological or hemodynamic) to the electrical stimulation is recordedand compared to the response prior to ablation. If the comparisonindicates an attenuation or absence of a response, the algorithm willindicate technical success of the ablation procedure.

If the comparison indicates an unsuccessful ablation procedure, thephysician or other health care provider may repeat the ablation therapyat the same site and/or repeat the therapy procedure for other nervetargets. Additional nerve targets could include bilateral ablation.

The console may include a graphical user interface configured to presentinformation from the physiological signals where the information is thephysiological response following (e.g., 5-60 seconds) the delivery oflow and/or high energy and; algorithms that compare the physiologicsignals to data from memory stored baseline values providing automatedselection of appropriate electrode configurations and/or the appropriateenergy delivery.

While certain forms of electrodes, or arrays/series of electrodes havebeen illustrated and described herein, it is not to be limited to thespecific forms or arrangement of parts described and shown.

Studies:

It is known that clinically beneficial effects can be obtained inpatients with heart failure by administering pharmacological therapies,such as nitroglycerine, to cause venodilation. These effects areimmediate and pronounced in magnitude to the point where they can leadto severe side effects of low systemic blood pressure and poor vitalorgan perfusion. Stimulation of the GSN results in a rapid and largeincrease in blood pressure through a reduction in splanchnic vascularcompliance, for example as shown by the experiment illustrated by FIG.14. Thus, it was reasonable to be concerned that reduction in GSNactivity by resection or ablation of the GSN could lead to the oppositeeffect, specifically to venodilation of the splanchnic circulation,resulting in a large, abrupt reduction in blood pressure and cardiacpreload similar to that observed with pharmacological therapy.

An animal experiment was conducted to examine the worst case scenario,or total reduction in GSN activity, by cutting the GSN. A sharp,immediate reduction in blood pressure was anticipated. However,unexpectedly and counterintuitively, cutting of the GSN instead resultedin a slow, progressive reduction in pressures with unexpected beneficialchanges in other hemodynamic measures.

Vascular capacitance can be increased in dogs with rapid pacing- inducedheart failure by surgical resection or equivalent but less invasivepercutaneous (through the chest wall) or transvenous ablation of a leftor right greater splanchnic nerve resulting in profound improvement ofcardiac function, pulmonary artery blood pressure and other relevanthemodynamic parameters. For the CHF patients such magnitude of changescan affect a number of clinical outcomes including mortality, exercisecapacity, need for hospitalization and quality of life. While there mayalso be a place for controlled or intermittent inhibition of GSNactivity in some patients, complete reduction in GSN activity may causephysiological changes that can result in clinically significant benefitsin patients with heart failure and/or other diseases associated withfluid overload without the immediate side effects frequently seen withpharmacological therapy. Ablation of a nerve caused by an ablationcatheter is envisioned to impede or eliminate signal transfer through anerve similar to that caused by surgical resection.

While at least one exemplary embodiment of the present invention(s) isdisclosed herein, it should be understood that modifications,substitutions and alternatives may be apparent to one of ordinary skillin the art and can be made without departing from the scope of thisdisclosure. This disclosure is intended to cover any adaptations orvariations of the exemplary embodiment(s). In addition, in thisdisclosure, the terms “comprise” or “comprising” do not exclude otherelements or steps, the terms “a” or “one” do not exclude a pluralnumber, and the term “or” means either or both. Furthermore,characteristics or steps which have been described may also be used incombination with other characteristics or steps and in any order unlessthe disclosure or context suggests otherwise. This disclosure herebyincorporates by reference the complete disclosure of any patent orapplication from which it claims benefit or priority.

1-60. (canceled)
 61. A method of ablating a greater splanchnic nerve totreat a patient diagnosed with heart failure, comprising: positioning anendovascular catheter comprising a proximal region, a flexible shaft,and a distal region, wherein the flexible shaft connects the proximaland distal regions and has a length adapted and sufficient to access anazygos vein space of a T9, T10 or T11 thoracic vertebra of the patientrelative to an access location when the proximal region remains externalto the patient, the distal region comprising one or more ablationelements; advancing the distal region through an azygous vein; advancingthe distal region from the azygous vein at least partially into a T9,T10, or T11 intercostal vein; activating the one or more ablationelements; delivering ablative energy to a greater splanchnic nerve usingthe one or more ablation elements while the distal region is at leastpartially in the T9, T10, or T11 intercostal vein; and removing theendovascular catheter from the patient.
 62. The method of claim 61,further comprising confirming a proper position of the one or moreablation elements in the T9, T10 or T11 intercostal vein.
 63. The methodof claim 61, further comprising confirming that the greater splanchnicnerve has been ablated.
 64. The method of claim 61, wherein the one ormore ablation elements comprises an inflatable balloon, the methodfurther comprising inflating the inflatable balloon in the T9, T10, orT11 intercostal vein.
 65. The method of claim 64, wherein the inflatableballoon has a cylindrically shaped inflated configuration, whereinexpanding the balloon comprises expanding the balloon towards thecylindrically shaped configuration.
 66. The method of claim 64, whereininflating the inflatable balloon comprises inflating the balloon to havea diameter from 2 mm-6 mm.
 67. The method of claim 61, furthercomprising distending a wall of the T9, T10, or T11 intercostal vein.68. The method of claim 61, wherein advancing the distal region from theazygous vein and at least partially into the T9, T10, or T11 intercostalvein comprises advancing the distal region at least partially into aright T9, T10, or T11 intercostal vein.
 69. The method of claim 61,wherein the method is a method for treating a patient diagnosed withheart failure with preserved ejection fraction.
 70. The method of claim61, further comprising, at a time subsequent to activating the one ormore ablation elements, assessing the patient's heart failure byassessing one or more of the patient's exercise capacity, bloodpressure, or neurohormonal changes.
 71. The method of claim 61, whereindelivering ablative energy to the greater splanchnic nerve causes anincrease in exercise tolerance.
 72. The method of claim 61, whereindelivering ablative energy to the greater splanchnic nerve causes adecrease in blood pressure.